FIELD OF THE INVENTION
This invention relates to methods for inhibiting neoplasms and their metastases. More particularly, this invention relates to methods employing the alteration of circadian prolactin rhythms to inhibit or ablate neoplasms and their metastases.
Prolactin and Circadian Rhythms
Research has demonstrated that circadian rhythms play important roles in regulating prolactin activities and vice versa.
Publications such as Meier, A. H., Gen. Comp. Endocrinol. 3(Suppl 1):488-508, 1972; Meier, A. H., Trans. Am. Fish. Soc. 113:422-431, 1984; Meier, A. H. et al., Current Ornithology II (ed Johnston R. E.) 303-343, 1984; Cincotta, A. H. et al., J. Endocrinol. 120:385-391, 1989; Meier, A. H., Amer. Zool. 15:905-916, 1975; Meier, A. H., Hormonal Correlates of Behavior (eds. Eleftherton and Sprott) 469-549, 1975 illustrate how circadian rhythms regulate prolactin activities. The resulting daily variations in responsiveness of various cell types to prolactin have a primary role in regulating numerous physiological processes, including fat storage, lipogenic responsiveness to insulin, migratory behavior, metamorphosis, reproduction, growth, pigeon cropsac development and mammary development (Meier, A. H., Gen. Comp. Endocrinol. 3(Suppl 1):488-508, 1972; Meier, A. H., Amer. Zool. 15:905-916, 1975; Meier, A. H. et al., Science 173:1240-1242, 1971). In regulating one of the foregoing physiological activities, prolactin may be observed to produce a stimulatory or an inhibitory effect on a given activity, or to have no effect on it. These varying effects have recently been shown in animals to be a function of the time of the daily endogenous peak (i.e. acrophase) of the rhythm of plasma prolactin concentration or a function of the time of daily injection of exogenous hormone (or of a substance that increases prolactin levels) or of the relation between endogenous peak and any induced peak. Further more, high levels of prolactin restricted to a discrete daily interval have a much greater physiologic (e.g. metabolic) effect in animals than do constant high levels throughout a day (Cincotta, A. H. et al., Horm. Metab. Res. 21:64-68, 1989; Borer, K. T. in The Hamster: Reproduction and Behavior (ed. Siegel, H. I.) 363-408, 1985). Such findings demonstrate the existence of daily response rhythms to prolactin by certain types of cells.
The first demonstration of a daily variation in physiological responsiveness to any hormone was the dramatic variation in fattening responsiveness to prolactin in the white-throated sparrow (Meier, A. H. et al., Gen. Comp. Endocrinol. 8:110-114, 1967). Injections at midday of a 16-hour daily photoperiod stimulated 3-fold increases in body fat levels, whereas injections given early in the photoperiod reduced fat stores by 50%. Such daily variations in fattening responses to prolactin were subsequently demonstrated in numerous species of all the major vertebrate classes (Meier, A. H., Amer. Zool. 15:905-916, 1975; Meier, A. H., Hormonal Correlates of Behavior (eds. Eleftherton and Sprott) 469-549, 1975) indicating the fundamental nature of such a temporal organization. The fattening response rhythm persists under constant light conditions (Meier, A. H. et al., Proc. Soc. Exp. Biol. Med. 137:408-415, 1971) indicating that it, like many other endogenous daily variations, is a circadian rhythm.
Additional studies have demonstrated that circadian rhythms have primary roles in regulating numerous physiologic activities, such as lipid metabolism and body fat stores (Meier, A. H. et al., Current Ornithology II (ed Johnston R. E.) 303-343, 1984; Meier, A. H., Amer. Zool. 15:905-916, 1975; Meier, A. H., Hormonal Correlates of Behavior (eds. Eleftherton and Sprott) 469-549, 1975; Meier, A. H. et al., J. Am. Zool. 16:649-659, 1976); Cincotta et al., Life Sciences 45:2247-2254, 1989; Cincotta et al., Ann. Nutr. Metab. 33:305-14, 1989; and Cincotta et al., Horm. Metabol. Res. 21:64-68, 1989. These experiments showed that an interaction of circadian rhythms of liporegulatory hormones (stimuli) and of circadian responses to these hormones (in target cells) determines amount of lipogenesis and fat storage. Thus, high plasma concentrations of prolactin (which serves as the stimulus) occur during the daily interval of maximal fattening responsiveness to prolactin in fat animals, but occur at other unresponsive times of day in lean animals (Meier, A. H., Amer. Zool. 15:905-916, 1975; Meier, A. H., Hormonal Correlates of Behavior (eds. Eleftherton and Sprott) 469-549, 1975; Speiler, R. E. et al., Nature 271:469-471, 1978). Similarly, plasma insulin (which acts as the stimulus) levels are highest during the daily interval of greatest hepatic lipogenic response to insulin in obese hamsters, but at a different time of day in lean hamsters (deSouza, C. J. et al., Chronobiol. Int. 4:141-151, 1987; Cincotta, A. H. et al., J. Endocr. 103:141-146, 1984). The phase relationships of these stimulus and response rhythms are believed to be expressions of neural circadian centers which in turn can be reset by neurotransmitter agents and hormone injections (including prolactin) to produce either fat or lean animals (Meier, A. H., Trans. Am. Fish. Soc. 113:422-431, 1984; Meier, A. H. et al., Current Ornithology II (ed Johnston R. E.) 303-343, 1984; Cincotta, A. H. et al., J. Endocrinol. 120:385-391, 1989; Emata, A. C. et al., J. Exp. Zool. 233:29-34, 1985; Cincotta, A. H. et al., Chronobiol. Int'l 10:244-258, 1993; Miller, L. J. et al., J. Interdisc. Cycles Res. 14:85-94, 1983). Accordingly, timed prolactin administration or enhancement has been shown to act directly upon tissues (e.g. liver in lipogenesis) undergoing circadian rhythms of responsiveness to the hormone to produce immediate variations in net physiologic effects (Cincotta, A. H. et al., Horm. Metab. Res. 21:64-68, 1989) and also acts indirectly by resetting one of the circadian neuroendocrine oscillations of a multi-oscillatory circadian pacemaker system to establish different phase relations between the multiple circadian (neural, hormonal, and tissue) expressions that control lipid metabolism (Meier, A. H., Trans. Am. Fish. Soc. 113:422-431, 1984; Meier, A. H. et al., Current Ornithology II (ed Johnston R. E.) 303-343, 1984; Cincotta, A. H. et al., J. Endocrinol. 120:385-391, 1989; Emata, A. C. et al., J. Exp. Zool. 233:29-34, 1985; Cincotta, A. H. et al., Chronobiol. Int'l 10:244-258, 1993; Miller, L. J. et al., J. Interdisc. Cycles Res. 14:85-94, 1983).
The present inventors have previously shown that prolactin, or substances that affect circulating prolactin levels, also affect circadian rhythms and in fact can be used to modify such rhythms (so that they more closely resemble the rhythms of lean, healthy, young individuals of the same sex) and to reset such rhythms (so that the modified rhythms persist in the modified condition). See, e.g. U.S. patent applications Ser. No. 08/158,153, now U.S. Pat. No. 5,468,755, 07/995,292, now U.S. Pat. No. 5,585,347, 07/999,685, abandoned, and U.S. Pat. No. 5,344,832. This prior work by the present inventors has been clinically tested in humans afflicted with various physiological disorders (obesity, diabetes, atherosclerosis, hypertension, immune dysfunction, and others) with good results.
In particular, in U.S. patent application Ser. No. 07/995,292, now U.S. Pat. No. 5,585,347 and in its continuation-in-part Ser. No. 08/264,558, now abandoned filed Jun. 23, 1994, the present inventors disclose a method for the reduction in a subject, vertebrate animal or human, of body fat stores, and reduction of at least one of insulin resistance, hyperinsulinemia, and hyperglycemia, and other metabolic diseases, especially those associated with Type II diabetes. More specifically, the foregoing application discloses methods for: (i) assessing the daily prolactin level cycles of a normal (healthy) human or vertebrate animal (free of obesity, disease or other disorder); (ii) diagnosing aberrant daily prolactin level cycles of a human or vertebrate animal; and (iii) determining the appropriate adjustments that need to be made to normalize such aberrant prolactin level cycles. This method involves the administration of at least one of a prolactin reducer and/or a prolactin enhancer at a first predetermined time (or times) within a 24-hour period (if only a prolactin reducer is administered) and/or at a second predetermined time (or times) of a 24-hour period (if a prolactin enhancer is administered). This therapy, when continued for several days, weeks or months, results in the long-term adjustment of aberrant or abnormal prolactin level cycles so that they conform to (or approach) normal prolactin level cycles. In most cases, this benefit persists over the long-term even after cessation of therapy. As a result, aberrant physiological parameters associated with various metabolic disorders are restored to normal levels or are modified to approach normal levels. Although this method is applied to all persons having aberrant prolactin levels during at least a portion of a 24-hour period, importantly, there is neither teaching of the possibility of applying it to persons with neoplastic disease, nor is there teaching of the possibility of applying this method to the treatment of neoplastic conditions.
Corticosterone and Circadian Rhythms
The secretory rates of corticosterone in humans is high in the early morning but low in the late evening. Plasma corticosterone levels range between a high of 0.2 mcg/ml an hour before waking in the morning and a low of about 0.05 mcg/ml around 12 AM. This effect is the result of a 24 hour cyclic alteration in the signals from the hypothalamus that cause corticosterone secretion. When a mammal changes sleep habits, the cycle changes correspondingly. Conversely, when the cycle changes, sleep habits are changed. Thus corticosterone administration can be used to synchronize the circadian rhythms of a number of experimental mammals which have been deprived of a photoperiod by exposure to constant light, as is done in the several of the Examples described below. The secretory pattern of corticosterone is different for each species but can easily be determined by assaying for the hormone at various time intervals during dark and light portions of the photoperiod.
While it was well known in the art that it was possible to control many metabolic disorders by adjustment of prolactin rhythms, it was completely surprising and unexpected to find that if prolactin rhythms in mammals afflicted with neoplasms and metastases were adjusted to conform to or approach the rhythms found in young, healthy, lean individuals of the same species and sex, neoplastic and metastatic growth was inhibited to a very significant extent.